Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution
Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower T...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/163562 |
| _version_ | 1826119410944835584 |
|---|---|
| author | Wang, Xiansong Hu, Wei Li, Xiangchun Huang, Dan Li, Qing Chan, Hung Zeng, Judeng Xie, Chuan Chen, Huarong Liu, Xiaodong Gin, Tony Wang, Maggie Haitian Cheng, Alfred Sze Lok Kang, Wei To, Ka-Fai Plewczynski, Dariusz Zhang, Qingpeng Chen, Xiaoting Chan, Danny Cheuk Wing Ko, Ho Wong, Sunny Hei Yu, Jun Chan, Matthew Tak Vai Zhang, Lin Wu, William Ka Kei |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Wang, Xiansong Hu, Wei Li, Xiangchun Huang, Dan Li, Qing Chan, Hung Zeng, Judeng Xie, Chuan Chen, Huarong Liu, Xiaodong Gin, Tony Wang, Maggie Haitian Cheng, Alfred Sze Lok Kang, Wei To, Ka-Fai Plewczynski, Dariusz Zhang, Qingpeng Chen, Xiaoting Chan, Danny Cheuk Wing Ko, Ho Wong, Sunny Hei Yu, Jun Chan, Matthew Tak Vai Zhang, Lin Wu, William Ka Kei |
| author_sort | Wang, Xiansong |
| collection | NTU |
| description | Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation. |
| first_indexed | 2024-10-01T04:59:32Z |
| format | Journal Article |
| id | ntu-10356/163562 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:59:32Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1635622022-12-09T04:13:13Z Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution Wang, Xiansong Hu, Wei Li, Xiangchun Huang, Dan Li, Qing Chan, Hung Zeng, Judeng Xie, Chuan Chen, Huarong Liu, Xiaodong Gin, Tony Wang, Maggie Haitian Cheng, Alfred Sze Lok Kang, Wei To, Ka-Fai Plewczynski, Dariusz Zhang, Qingpeng Chen, Xiaoting Chan, Danny Cheuk Wing Ko, Ho Wong, Sunny Hei Yu, Jun Chan, Matthew Tak Vai Zhang, Lin Wu, William Ka Kei Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Cancer Expression Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation. This work was supported by the Shenzhen Science and Technology Program (JCYJ20180508161604382) and Shenzhen Science and Technology Innovation Commission. D. Plewczynski was supported by Polish National Science Center (2014/15/B/ST6/05082) and Foundation for Polish Science (TEAM to D. Plewczynski) cofinanced by the European Union under the European Regional Development Fund. 2022-12-09T04:13:13Z 2022-12-09T04:13:13Z 2022 Journal Article Wang, X., Hu, W., Li, X., Huang, D., Li, Q., Chan, H., Zeng, J., Xie, C., Chen, H., Liu, X., Gin, T., Wang, M. H., Cheng, A. S. L., Kang, W., To, K., Plewczynski, D., Zhang, Q., Chen, X., Chan, D. C. W., ...Wu, W. K. K. (2022). Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution. Cancer Research, 82(8), 1482-1491. https://dx.doi.org/10.1158/0008-5472.CAN-21-3458 0008-5472 https://hdl.handle.net/10356/163562 10.1158/0008-5472.CAN-21-3458 35247889 2-s2.0-85128469757 8 82 1482 1491 en Cancer Research © 2022 American Association for Cancer Research. All rights reserved. |
| spellingShingle | Science::Medicine Cancer Expression Wang, Xiansong Hu, Wei Li, Xiangchun Huang, Dan Li, Qing Chan, Hung Zeng, Judeng Xie, Chuan Chen, Huarong Liu, Xiaodong Gin, Tony Wang, Maggie Haitian Cheng, Alfred Sze Lok Kang, Wei To, Ka-Fai Plewczynski, Dariusz Zhang, Qingpeng Chen, Xiaoting Chan, Danny Cheuk Wing Ko, Ho Wong, Sunny Hei Yu, Jun Chan, Matthew Tak Vai Zhang, Lin Wu, William Ka Kei Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution |
| title | Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution |
| title_full | Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution |
| title_fullStr | Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution |
| title_full_unstemmed | Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution |
| title_short | Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution |
| title_sort | single hit inactivation drove tumor suppressor genes out of the x chromosome during evolution |
| topic | Science::Medicine Cancer Expression |
| url | https://hdl.handle.net/10356/163562 |
| work_keys_str_mv | AT wangxiansong singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT huwei singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT lixiangchun singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT huangdan singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT liqing singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT chanhung singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT zengjudeng singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT xiechuan singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT chenhuarong singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT liuxiaodong singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT gintony singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT wangmaggiehaitian singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT chengalfredszelok singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT kangwei singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT tokafai singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT plewczynskidariusz singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT zhangqingpeng singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT chenxiaoting singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT chandannycheukwing singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT koho singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT wongsunnyhei singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT yujun singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT chanmatthewtakvai singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT zhanglin singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution AT wuwilliamkakei singlehitinactivationdrovetumorsuppressorgenesoutofthexchromosomeduringevolution |